Bioprinting 3D skin for patient-specific drug discovery in inflammatory skin diseases.

生物打印 3D 皮肤，用于炎症性皮肤病患者特定药物的发现。

• 批准号: 9571254
• 负责人: Angela M Christiano
• 金额: $ 63.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9571254
• 关键词: Address; Adverse effects; Affect; Allogenic; Animal Disease Models; Autologous; Biocompatible Materials; Biological Assay; Biological Models; Biological Products; Blood Cells; CRISPR/Cas technology; Calcineurin inhibitor; Cell Line; Cell Lineage; Cells; Collaborations; Complex; Cyclosporine; Development; Disease; Disease model; Drug Modelings; Drug Screening; Endothelial Cells; Epidermolysis Bullosa; Extramural Activities; Fibroblasts; Gene Expression; Genes; Goals; Histology; Homing; Immune; Immunocompetent; Individual; Inflammation; Inflammatory; Methodology; Modeling; Monitor; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Population; Psoriasis; Reporter; Reproducibility; Research Personnel; Retinoids; Rodent; Safety; Skin; Source; Structure; T-Lymphocyte; Techniques; Technology; Testing; Tissues; Validation; adalimumab; bioprinting; cell type; chronic inflammatory skin; cytokine; design; drug candidate; drug development; drug discovery; high throughput screening; human tissue; imaging system; immune function; improved; in vitro Model; induced pluripotent stem cell; innovation; keratinocyte; melanocyte; novel therapeutics; personalized medicine; skin disorder; therapy outcome; three-dimensional modeling; tool; treatment response

Project Summary Psoriasis is an inflammatory skin disorder with abnormal epidermal hyperproliferation, which affects 2-3 % of the US population. There are no reliable in vitro models with which the efficacy and safety of psoriasis drug candidates can be tested. To meet this major unmet pharmaceutical need, we will combine iPSC reprograming and 3D bioprinting technologies to construct a 3D skin model to screen for drugs to treat this disease. iPSC methodology will be used, because iPSCs have unlimited proliferation potential and the capability to differentiate into different cell lineages, which allows us to circumvent the limitation imposed by the limited availability of primary cells that can be procured from patients. We successfully constructed 3D skin using exclusively iPSC-derived cells (fibroblasts and keratinocytes), demonstrating the feasibility of this approach. 3D bioprinting can allow us to reproducibly construct complex structures to recapitulate human tissues/organs. In this project, we will first construct immunocompetent 3D skin with primary keratinocytes, fibroblasts and T cells. Then, iPSCs will be reprogramed from fibroblasts or blood cells obtained from normal and psoriatic individuals. Keratinocytes and fibroblasts will be differentiated from iPSCs for construction of 3D skin models, whereas the abundant availability of T cells allows us to use cells directly from primary sources. Bioprinted psoriasis-specific iPSC derived skin constructs will be used for disease modeling and pharmacological validation. CRISPR technology will be used to integrate fluorescent reporters in iPSC-derived keratinocytes to monitor disease induction of psoriasis and effect of drug treatment. Completion of this project will provide us with a reliable 3D bioprinted model to develop drugs to treat psoriasis. Moreover, our 3D skin model can be easily adapted and modified to screen for drugs to treat other skin diseases, using a platform approach.

项目概要 银屑病是一种伴有异常表皮过度增殖的炎症性皮肤病，影响 2-3% 的患者 美国人口。目前尚无可靠的体外模型来验证银屑病药物的疗效和安全性 候选人可以接受测试。为了满足这一未满足的重大制药需求，我们将结合 iPSC 重新编程和 3D 生物打印技术构建 3D 皮肤模型来筛选治疗该疾病的药物 疾病。将使用 iPSC 方法，因为 iPSC 具有无限的增殖潜力，并且 分化成不同细胞谱系的能力，这使我们能够规避细胞所施加的限制 从患者处获得的原代细胞有限。我们成功构建了3D皮肤 仅使用 iPSC 衍生细胞（成纤维细胞和角质形成细胞），证明了这种方法的可行性 方法。 3D生物打印可以让我们可重复地构建复杂的结构来概括人类 组织/器官。在这个项目中，我们将首先用原代角质形成细胞构建具有免疫活性的3D皮肤， 成纤维细胞和T细胞。然后，iPSC 将从正常人获得的成纤维细胞或血细胞中重新编程。 和牛皮癣患者。角质形成细胞和成纤维细胞将从 iPSC 中分化出来，用于构建 3D 皮肤模型，而 T 细胞的丰富可用性使我们能够直接使用来自主要来源的细胞。 生物打印的银屑病特异性 iPSC 衍生皮肤结构将用于疾病建模和 药理学验证。 CRISPR 技术将用于在 iPSC 衍生中整合荧光报告基因 角质形成细胞监测牛皮癣的疾病诱导和药物治疗的效果。本项目完成情况 将为我们提供可靠的3D生物打印模型来开发治疗牛皮癣的药物。此外，我们的 3D 皮肤 使用平台可以轻松调整和修改模型，以筛选治疗其他皮肤病的药物 方法。